4-54263664-C-T

Position:

chr4-54263664-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_006206.6(PDGFRA):c.368-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,612,354 control chromosomes in the GnomAD database, including 3,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 226 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3411 hom. )

Consequence

PDGFRA
NM_006206.6 splice_region, intron

Scores

Splicing: ADA: 0.02828

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.39

Variant links:

Genes affected

PDGFRA (HGNC:8803): (platelet derived growth factor receptor alpha) This gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, Mar 2012]

PDGFRA links:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.21).

BP6

Variant 4-54263664-C-T is Benign according to our data. Variant chr4-54263664-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-54263664-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRA	NM_006206.6 linkuse as main transcript	c.368-3C>T		splice_region_variant, intron_variant		ENST00000257290.10	NP_006197.1	P16234-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRA	ENST00000257290.10 linkuse as main transcript	c.368-3C>T		splice_region_variant, intron_variant		1	NM_006206.6	ENSP00000257290.5		P16234-1
ENSG00000282278	ENST00000507166.5 linkuse as main transcript	c.1018-11261C>T		intron_variant		2		ENSP00000423325.1		A0A0B4J203

Frequencies

GnomAD3 genomes

AF:

0.0461

AC:

7019

AN:

152126

Hom.:

226

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0423

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0406

Gnomad FIN

AF:

0.0607

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0709

Gnomad OTH

AF:

0.0436

GnomAD3 exomes

AF:

0.0488

AC:

12265

AN:

251276

Hom.:

405

AF XY:

0.0504

AC XY:

6844

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0348

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0478

Gnomad FIN exome

AF:

0.0628

Gnomad NFE exome

AF:

0.0684

Gnomad OTH exome

AF:

0.0489

GnomAD4 exome

AF:

0.0646

AC:

94328

AN:

1460110

Hom.:

3411

Cov.:

AF XY:

0.0644

AC XY:

46750

AN XY:

726448

show subpopulations

Gnomad4 AFR exome

AF:

0.00938

Gnomad4 AMR exome

AF:

0.0270

Gnomad4 ASJ exome

AF:

0.0347

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0490

Gnomad4 FIN exome

AF:

0.0653

Gnomad4 NFE exome

AF:

0.0726

Gnomad4 OTH exome

AF:

0.0556

GnomAD4 genome

AF:

0.0461

AC:

7015

AN:

152244

Hom.:

226

Cov.:

AF XY:

0.0455

AC XY:

3388

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0118

Gnomad4 AMR

AF:

0.0422

Gnomad4 ASJ

AF:

0.0332

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0406

Gnomad4 FIN

AF:

0.0607

Gnomad4 NFE

AF:

0.0709

Gnomad4 OTH

AF:

0.0427

Alfa

AF:

0.0587

Hom.:

168

Bravo

AF:

0.0409

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0649

EpiControl

AF:

0.0636

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 27884173, 20169295) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Gastrointestinal stromal tumor

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Idiopathic hypereosinophilic syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.028

dbscSNV1_RF

Benign

0.046

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over